Long-term efficacy and safety of tenofovir disoproxil fumarate in HIV-1-infected adolescents failing antiretroviral therapy: the final results of study GS-US-104-0321.

BACKGROUND: Reports of long-term tenofovir disoproxil fumarate (TDF) treatment in HIV-infected adolescents are limited. We present final results from the open-label (OL) TDF extension following the randomized, placebo (PBO)-controlled, double-blind phase of GS-US-104-0321 (Study 321). METHODS: HIV-infected 12- to 17-year-olds treated with TDF 300 mg or PBO with an optimized background regimen (OBR) for 24-48 weeks subsequently received OL TDF plus OBR in a single arm study extension. HIV-1 RNA and safety, including bone mineral density (BMD), was assessed in all TDF recipients. RESULTS: Eighty-one subjects received TDF (median duration 96 weeks). No subject died or discontinued OL TDF for safety/tolerability. At week 144, proportions with HIV-1 RNA <50 copies/mL were 30.4% (7 of 23 subjects with baseline HIV-1 RNA >1000 c/mL initially randomized to TDF), 41.7% (5 of 12 subjects with HIV-1 RNA <1000 c/mL who switched PBO to TDF) and 0% (0 of 2 subjects failed randomized PBO plus OBR with HIV-1 RNA >1000 c/mL and switched PBO to TDF). Viral resistance to TDF occurred in 1 subject. At week 144, median decrease in estimated glomerular filtration rate was 38.1 mL/min/1.73 m (n = 25). Increases in median spine (+12.70%, n = 26) and total body less head BMD (+4.32%, n = 26) and height-age adjusted Z-scores (n = 21; +0.457 for spine, +0.152 for total body less head) were observed at week 144. Five of 81 subjects (6%) had persistent >4% BMD decreases from baseline. CONCLUSIONS: Some subjects had virologic responses to TDF plus OBR, and TDF resistance was rare. TDF was well tolerated and can be considered for treatment of HIV-infected adolescents.

Efficacy and safety of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents: 5 years of experience.

BACKGROUND: To evaluate the long-term (up to week 292) safety, efficacy and tolerability of ritonavir-boosted tipranavir in HIV-1-infected pediatric patients. Long-term follow up of patients enrolled in the randomized, open-label pediatric trial (1182.14/PACTG1051). METHODS: HIV-1-infected pediatric patients (2-18 years) who participated in the PACTG 1051 trial were followed for ritonavir-boosted tipranavir-based regimen efficacy, safety and tolerability through week 292. RESULTS: In patients <12 years of age, 51/62 (82%) were receiving drug at week 48 and 13/62 (21%) at week 288. Among adolescents (12-18 years of age), 35/53 (66%) were receiving drug at week 48 and 2/53 (4%) at week 288. Among patients 2 to <6 years of age, 18/25 (72%) had viral loads <400 copies/mL at week 48. By week 292, 9/25 (36%) of patients had viral loads <400 copies/mL. Among older patients, week 48 responder rates were 35% (13/37 of patients 6 to <12 years of age) and 32% (17/53 of patients 12 to 18 years of age). By week 292, 6/37 (16%) of those 6 to <12 years of age and 2/53 (4%) of those 12 to 18 years of age had viral loads <400 copies/mL. Overall safety and tolerability profiles were best for children who initiated treatment between 2 and <6 years of age. Drug-related adverse events (investigator defined) were similar across all age groups (55-65%). CONCLUSIONS: Pediatric patients who begin treatment at the earlier ages, and who are stable on a ritonavir-boosted tipranavir-based regimen at week 48, generally continue to demonstrate good safety, tolerability and virologic efficacy profiles up to 292 weeks of treatment.

A randomized study of tenofovir disoproxil fumarate in treatment-experienced HIV-1 infected adolescents.

BACKGROUND: There are few data on the safety and antiviral activity of tenofovir disoproxil fumarate (TDF) in HIV-1 infected adolescents. METHODS: A randomized, double-blinded, placebo-controlled study was conducted. Ninety adolescents (12 to <18 years) who were viremic while receiving antiretroviral treatment were randomized to receive TDF 300 mg (mean, 216.8 mg/m(2)) or placebo in combination with an optimized background regimen (OBR) for 48 weeks. The primary efficacy endpoint was time-weighted average change in plasma HIV-1 RNA from baseline at week 24 RESULTS: Eighty-seven subjects (45 TDF, 42 placebo) received the study drug. Through week 24, the median time-weighted average change in plasma HIV-1 RNA was not different between the TDF and placebo groups (-1.6 versus -1.6 log(10)copies/mL, P = 0.55). The percentages of subjects who achieved HIV-1 RNA <400 copies/mL were similar at week 24 (40.9 versus 41.5%). One fourth of subjects in the TDF and placebo groups (24.4 versus 28.6%) had at least 3 active agents in the OBR. Many subjects in both groups had baseline genotypic resistance to TDF (48.9 versus 33.3%). TDF was generally safe and well tolerated. There were no statistically significant differences in changes of renal function and bone mineral density between the 2 groups. CONCLUSION: This study of TDF in combination with an OBR in antiretroviral-experienced adolescents did not meet its primary or secondary efficacy endpoints. The effectiveness of the OBR and baseline genotypic resistance to TDF in both groups may have confounded the efficacy findings. No clinically relevant TDF-related renal or bone toxicities were observed in this adolescent population.